Glucocorticoids are potent suppressors of the immune response and inflammation. The effects of glucocorticoids are mediated by the glucocorticoid receptor, which is a member of the hormone receptor superfamily. The objective of this research proposal is to elucidate the manner by which glucocorticoids and the glucocorticoid receptor act to antagonize pro-inflammatory processes mediated by cytokines and various transcription factors. Recently, we have identified a peptide through combinatorial phage display that binds to GR and inhibits both exogenous and endogenous GR activity. To strengthen our knowledge of GR pharmacology, we propose to utilize this peptide to define which surfaces on GR are functionally important in mediating immune and inflammatory processes. Additionally, we propose to identify novel proteins that interact with the functionally important surfaces of GR. With this knowledge, we hope to elucidate the GR signaling pathway and shed new light on the role of GR in immune and inflammatory processes. To accomplish these objectives, we propose the following three specific aims: Specific Aim 1: Utilize peptide antagonists to study the mechanism(s) by which GR regulates cellular pathways in response to different ligands. Specific Aim 2: Identify and define the functional significance of specific surfaces exposed on GR upon ligand binding. Specific Aim 3: Identify proteins that interact with functionally important surfaces on GR.